Polycomb Repressive-Deubiquitinase Complex Safeguards Oocyte Epigenome and Female Fertility by Restraining Polycomb Activity [CUT&RUN]

Polycomb group proteins are essential for oogenesis, yet mechanisms underlying the non-canonical Polycomb landscapes in oocytes remain unclear. Here we report BAP1, a core component of the Polycomb Repressive-Deubiquitinase (PR-DUB) complex, as a key negative regulator of Polycomb activity during oogenesis. BAP1 restricts pervasive H2AK119ub1 accumulation in oocytes and protects oocyte-specific broad H3K27ac, particularly within gene-poor regions, from ectopic H3K27me3 deposition. While PR-DUB has been linked to gene repression, in oocytes BAP1 primarily promotes transcription and contributes minimally to Polycomb-mediated silencing. BAP1-deficient oocytes cannot support preimplantation development due to impaired maternal-to-zygotic transition and defective embryonic enhancer activation. Notably, aberrant H3K27me3 landscape established in BAP1-null oocytes persists into early embryos. Together, these findings reveal a critical role for PR-DUB in safeguarding the oocyte epigenome by protecting euchromatin from ectopic Polycomb activity, rather than enforcing transcriptional repression.